In the course of recent studies in our laboratory designed to assess the effects of insulin on cardiac contractility the relationship between catechol stimulation and the effects of insulin was examined. It was found that if the muscle was first exposed to insulin the magnitude of responses to norepinephrine were reduced by about 50%. This led us to consider the possibility that insulin might serve to protect the myocardium from cellular injury induced by catecholamines. And conversely, the absence of insulin might render the myocardium more vulnerable to this injury. A pilot study was undertaken with a limited number of animals using a rabbit model. A striking difference was found consistent with this hypothesis. The proposed investigations have been divided into two major divisions. In the first segment, the objectives will be to characterize the myocardial lesions histologically and histochemically and to assess dose-response relations. Temporal factors which relate to the evolution of lesions and modifications produced by insulin at various intervals before and following the onset of injury will be determined. A piglet model will also be used to assess changes in coronary flow and myocardial metabolism which relate to catechol injury and modification by insulin. The second portion of this study will be directed to investigations with alloxan diabetic rabbit and piglet models. It will be determined if insulin deficient animals demonstrate a potentiation of norepinephrine induced myocardial lesions. Conversely, the protocol has been arranged to determine if insulin administration affords protection in the insulin-deficient model. Quantification of muscle injury will be accomplished with a radionuclide method using technetium-99m and CPK enzyme analysis. In addition, mechanical performance of isolated cardiac muscle strips from these models will be studied to assess contractile strength and responsiveness to insulin and norepinephrine.